BIOLOGY OF METASTASIS IN BREAST CANCER PATIENTS Metastasis is the major cause of death in breast cancer patients, but the molecular nature of metustatic breast cancer is poorly understood. This limited understanding is likely due to the genetic complexity of the metastatic phenotype, which is not easily studied using traditional methods. Little is known at the genomewide level about the degree of heterogeneity that may exist within primary tumors or the relationship of this heterogeneity to eventual metastasis. Few studies have compared paired metastatic lesions and primary tumors;furthermore, most of these studies have been limited to the analysis of single or few molecular markers. Thus, the debate over whether a stochastic versus deterministic model of cancer metastasis is most relevant in breast cancer remains largely unresolved. A comprehensive understanding of the mechanisms of metastasis would greatly accelerate progress in the development of new diagnostic and therapeutic approaches to advanced breast cancer. Our long-term goal is to develop a more accurate understanding of the genetic alterations associated with progression of human breast cancer, through a systematic, genome-wide analysis of primary and metastatic lesions in patients with breast cancer. In addition, we will assess whether patterns of genetic alteration encoded in the primary tumor predispose to site-specific metastasis. To achieve these goals, we propose the following Aims: Specific Aim 1. To determine the degree and nature of genetic relatedness between paired primary and metastatic lesions in human breast cancer patients using SNP microarrays. Specific Aim 2. To develop predictive models for site of eventual metastasis using DNA microarray-based gene expression profiling of primary breast tumors.